Supervisors:
Professor Anne Donaldson - University of Aberdeen, School of Medicine, Medical Sciences and Nutrition - [Email Address Removed]
Dr Riko Hatakeyama - University of Aberdeen, School of Medicine, Medical Sciences and Nutrition - [Email Address Removed]
The goal of this project is to understand cellular mechanisms that protect genome stability, essential for the survival of any organism.
Genome stability requires AGC kinases, one of the best-characterized subgroups of kinases, as demonstrated in the yeast model (PMID: 24035500). However, the phosphorylation substrate(s) mediating this important function of AGC kinases remains unknown.
Recently, phosphorylation of human ribonucleotide reductase (RNR), a rate-limiting enzyme in DNA synthesis, was found to be essential for genome stability (PMID: 34126361). Because this phosphorylation required TOR complex 2, an activator of AGC kinases, we hypothesize that AGC kinases stabilize the genome by phosphorylating RNR. In support of this hypothesis, the surrounding amino acid sequence of the RNR’s phosphosite, which is strictly conserved from yeast to human, matches the consensus motif of AGC kinase substrates (RXXS/T). The student will test this hypothesis, in both yeast and human cell models, using multiple techniques in biochemistry (e.g., in vitro kinase assay), genetics (e.g., phospho-deficient/mimicking mutagenesis) and molecular biology (e.g., DNA fiber assay).
Long-term, this project can be translated to a new therapeutic strategy against cancer; because genome stability is a proven Achilles’s heel of cancer cells, AGC kinase inhibitors, particularly in combination with DNA-damaging reagents, may effectively kill cancer cells. In the long-term we aim to test this possibility against a wide range of cancer cell lines, utilizing a third party’s cell panel screening service.
This is an interdisciplinary project combining the world-leading expertise of Prof Donaldson (current recipient of a CRUK programme grant) in chromosome biology, Dr Hatakeyama (current recipient of a BBSRC New Investigator grant) in TOR signalling, and Prof Alessi (the director of MRC-PPU) in AGC kinases.
This project holds a huge training potential because many labs and companies, world-wide, work on AGC kinases, which perform multiple essential functions in cell survival, proliferation, and cancer development; therefore, the knowledge and experience on this kinase family will place the student at a strong position in both academic and industrial job markets.
The principal supervisor’s lab runs weekly joint meetings involving neighboring labs working on related disciplines in cell biology (chromosome biology, cell cycle, signal transduction, membrane trafficking, cancer biology and fungal pathogenesis); via attending these meetings, the student will grow as a highly valuable professional equipped with broad knowledge and perspective in cell biology.
Application Procedure:
Please visit this page for full application information: http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [Email Address Removed]
Two references should be provided by the deadline using the EASTBIO reference form.
Please advise your referees to return the reference form to [Email Address Removed]
Unfortunately due to workload constraints, we cannot consider incomplete applications
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